TLR4 deletion reduces small fiber sensory abnormalities and nerve degeneration in diabetic male mice

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes, significantly impairing quality of life and lacking effective disease-modifying treatments. Chronic inflammation involving toll-like receptor 4 (TLR4) has been implicated in diabetes and neuropathy development. TLR4 is an innate immune receptor that triggers an inflammatory response, leading to the production of pro-inflammatory cytokines. While TLR4 has been studied in various neuropathy models, its role in diabetic neuropathy and its effect on nerve fiber integrity remains unclear. To investigate the impact of TLR4 on DPN, we induced diabetes in wild-type and TLR4 knockout (TLR4-/-) mice using streptozotocin. Groups contained 8-18 animals and were approximately half male and half female. Over six weeks, we assessed blood glucose, weight changes, thermal and mechanical sensory function, hind paw intraepidermal nerve fiber density (IENFD), dermal macrophage accumulation, and serum cytokines. In males, TLR4 deletion protected against STZ-induced thermal hyposensitivity, decreases in IENFD, and dermal macrophage accumulation. Female mice developed less severe hyperglycemia and were resistant to neuropathic changes, making the protective effects of TLR4 deletion less pronounced in females than in males. Our findings confirm that TLR4 plays a role in DPN pathogenesis in a diabetic mouse model, demonstrating that its deletion promotes sensory function and preserves IENFD in males. These results highlight TLR4 as a potential therapeutic target for slowing the progression of neuropathy in diabetes. Our data also emphasizes the need for further research into the role of sex-specific disease mechanisms in DPN.